Some forms of amyotrophic lateral sclerosis (ALS) are caused by mutations in the copper-zinc superoxide dismutase (SOD) gene. It is currently unclear how these mutations selectively lead to motor neuron death. Loss of SOD activity does not always result from these mutations. It has been proposed that mutations in SOD give the enzyme some new function that is specifically toxic to motor neurons. One possibility is that mutations in SOD promote aberrant protein-protein interactions which selectively destroy motor neurons. It is possible to create linked SOD dimers, with normal enzymatic activity, which are expressed as a single polypeptide. This will facilitate the biochemical analysis of normal/mutant heterodimers, which are the most prevalent form of SOD in ALS cells, in the absence of the normal and mutant homodimers. Using linked SOD dimers in the yeast interaction trap two-hybrid system will identify aberrant in-vivo protein-protein interactions. Any expressed cDNAs found to interact with mutant SOD dimers will be candidate genes for other forms of ALS. These experiments should lead to a better understanding of how mutations in SOD lead to the development of ALS.